HBV is the most common risk factor for HCC development, accounting for almost 50% of cases worldwide. Despite significant advances in immunotherapy, there is limited information on the HBV-HCC tumor microenvironment (TME), which may influence the response to checkpoint inhibitors. Here, we characterize the TME in a unique series of liver specimens from HBV-HCC patients to identify who might benefit from immunotherapy. By combining an extensive immunohistochemistry analysis with the transcriptomic profile of paired liver samples (tumor vs. nontumorous tissue) from 12 well-characterized Caucasian patients with HBV-HCC, we identified two distinct tumor subtypes that we defined immune-high and immune-low. The immune-high subtype, seen in half of the patients, is characterized by a high number of infiltrating B and T cells in association with stromal activation and a transcriptomic profile featuring inhibition of antigen presentation and CTL activation. All the immune-high tumors expressed high levels of CTLA-4 and low levels of PD-1, while PD-L1 was present only in four of six cases. In contrast, the immune-low subtype shows significantly lower lymphocyte infiltration and stromal activation. By whole exome sequencing, we documented that four out of six individuals with the immune-low subtype had missense mutations in the CTNNB1 gene, while only one patient had mutations in this gene in the immune-high subtype. Outside the tumor, there were no differences between the two subtypes. This study identifies two distinctive immune subtypes in HBV-associated HCC, regardless of the microenvironment observed in the surrounding nontumorous tissue, providing new insights into pathogenesis. These findings may be instrumental in the identification of patients who might benefit from immunotherapy.
乙型肝炎病毒是肝细胞癌发生最常见的危险因素，约占全球病例的50%。尽管免疫治疗取得显著进展，但关于乙型肝炎病毒相关肝细胞癌肿瘤微环境的信息有限，而该微环境可能影响对检查点抑制剂的治疗反应。本研究通过对一组独特的乙型肝炎病毒相关肝细胞癌患者肝脏标本进行肿瘤微环境特征分析，以识别可能从免疫治疗中获益的患者群体。通过对12例特征明确的白种人乙型肝炎病毒相关肝细胞癌患者的配对肝脏样本（肿瘤组织与非肿瘤组织）进行全面的免疫组织化学分析和转录组学检测，我们鉴定出两种不同的肿瘤亚型，分别定义为免疫高表达型和免疫低表达型。在占患者总数一半的免疫高表达型中，其特征表现为大量B细胞和T细胞浸润伴随基质活化，其转录组学特征显示抗原呈递和细胞毒性T淋巴细胞活化受到抑制。所有免疫高表达型肿瘤均呈现高水平的CTLA-4表达和低水平的PD-1表达，而PD-L1仅在六例中的四例中检测到。相比之下，免疫低表达型亚型则显示出显著降低的淋巴细胞浸润和基质活化程度。通过全外显子组测序，我们发现六例免疫低表达型患者中有四例存在CTNNB1基因错义突变，而免疫高表达型亚型中仅有一例患者存在该基因突变。在肿瘤区域外，两种亚型间未发现显著差异。本研究首次在乙型肝炎病毒相关肝细胞癌中鉴定出两种特征鲜明的免疫亚型，且该分型与周围非肿瘤组织的微环境特征无关，为疾病发病机制提供了新的见解。这些发现可能有助于识别潜在受益于免疫治疗的患者群体。
肿瘤(癌症)患者之家